DESCRIPTION: Despite optimal antiretroviral therapy (ART), HIV-infected individuals continue to have an increased risk of mortality and several aging-associated morbidities than the general population. The chronic inflammatory state of treated HIV infection appears to predict many of these morbidities and is also thought to lead to premature immunosenescence, functional T cell defects typically seen in much older HIV-uninfected individuals. However, the specific T cell defects that impair functional immune responses in treated HIV infection are unknown and may be quite distinct from those observed in aging. Preliminary data from our group suggests that the proliferative history marker CD57 is abnormally low on effector CD28- CD8+ T cells in HIV-infected individuals, increases during suppressive ART, but fails to normalize. This persistently low CD57 defect during ART is associated with monocyte activation and indoleamine 2,3-dioxygenase (IDO) induction, known drivers of proliferative T cell defects, and strongly predicts increased mortality in this setting. These CD8+ T cell defects are quite distinct from aging-associated immunosenescence, which is typically characterized by increased CD57 on effector CD8+ T cells. These data motivated the hypothesis that the phenotypic T cell defects responsible for functional adaptive immune defects in treated HIV disease are quite distinct from those observed in elderly HIV-infected individuals. We will address this hypothesis directly in a cohort of 200 HIV-infected and 100 HIV-uninfected individuals with the following specific aims: 1) To determine whether HIV-infected individuals maintaining ART-mediated viral suppression have poorer vaccine responsiveness than age-matched HIV-uninfected individuals and whether these defects can be reversed by early initiation of ART, 2) to characterize the phenotypic T cell defects that predict poor vaccine responsiveness in both treated HIV infection and aging, and 3) to characterize the relationship between innate immune activation pathways and poor vaccine responsiveness in treated HIV infection and aging. By characterizing the immunologic determinants of impaired vaccine responsiveness in treated HIV infection and how they may differ from those of aging-associated immunosenescence, this project will help identify targets for novel interventions to restore immune function and health in HIV-infected individuals.